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Decreased Phosphorylation and Increased Methionine Oxidation of α-Synuclein in the Methionine Sulfoxide Reductase A
Derek B Oien1, Gonzalo A Carrasco, Jackob Moskovitz
1Department of Pharmacology and Toxicology, School of Pharmacy, The University of Kansas, Lawrence, KS 66045, USA.
Abstract:
Previously, we have showed that overexpression of methionine-oxidized α-synuclein in methionine sulfoxide reductase A (MsrA) null mutant yeast cells inhibits α-synuclein phosphorylation and increases protein fibrillation. The current studies show that ablation of mouse MsrA gene caused enhanced methionine oxidation of α-synuclein while reducing its own phophorylation levels, especially in the hydrophobic cell-extracted fraction. These data provide supportive evidence that a compromised MsrA function in mammalian brain may cause enhanced pathologies associated with altered α-synuclein oxidation and phosphorylation levels.
Insights
Methionine sulfoxide reductase A (MsrA) deficiency enhances alpha-synuclein oxidation and reduces its phosphorylation. This suggests compromised MsrA function may contribute to brain pathologies linked to alpha-synuclein alterations.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Alpha-synuclein (α-synuclein) aggregation and altered phosphorylation are implicated in neurodegenerative diseases.
- Methionine oxidation is a post-translational modification of α-synuclein.
- Methionine sulfoxide reductase A (MsrA) repairs oxidized methionine residues.
Purpose of the Study:
- To investigate the role of MsrA in regulating α-synuclein oxidation and phosphorylation in vivo.
- To determine if compromised MsrA function contributes to α-synuclein-related pathologies.
Main Methods:
- Utilized MsrA knockout (KO) mouse models.
- Analyzed α-synuclein methionine oxidation and phosphorylation levels in brain extracts.
- Fractionated cell extracts to examine specific cellular compartments.
Main Results:
- Ablation of the MsrA gene in mice led to increased methionine oxidation of α-synuclein.
- MsrA deficiency resulted in reduced α-synuclein phosphorylation, particularly in hydrophobic fractions.
- Previous studies in yeast showed similar effects of MsrA on α-synuclein.
Conclusions:
- Compromised MsrA function in the mammalian brain enhances α-synuclein methionine oxidation.
- Reduced α-synuclein phosphorylation in MsrA-deficient brains suggests a link between oxidation and phosphorylation.
- These findings support the hypothesis that altered MsrA activity contributes to neurodegenerative pathologies via α-synuclein modifications.
